Process for preparing urethane compound for medical instruments

ABSTRACT

A process for preparing an urethane compound for medical instruments, characterized by reacting a hydroxyl compound (A) with an isocyanate compound (B) in the absence of a catalyst or in the presence of a reaction catalyst other than an organic tin compound to give an urethane compound (I). According to the process, the urethane compound showing high safety can be easily prepared, in particular, while molecular weight of the compound is controlled.

This application is of continuation of Ser. No. 09/608,004, filed Jun.30, 2000, and issued an U.S. 6,495,651

BACKGROUND OF THE INVENTION

The present invention relates to a process for preparing an urethanecompound for medical instruments. More particularly, the presentinvention relates to a process for easily preparing an urethane compound(macromonomer) showing high safety, which is very useful for a materialof medical instruments represented by optical materials such as acontact lens material and an intraocular lens material. Furthermore, thepresent invention relates to a process for preparing an urethanecompound while molecular weight of the compound is controlled.

At present, various urethane compounds such as urethane foam, urethanerubber, adhesives and polyurethane synthetic fiber are industriallyused.

In the absence of a catalyst or in the presence of a compound such as anorganic metal compound or a tertiary amine, hydroxyl group is reactedwith isocyanate group to form urethane bond. Particularly, from theviewpoint of high catalytic activity, the organic metal compounds aregenerally used. Among them, an organic tin compound is well known.

However, it is considered that the organic tin compound which isgenerally known as a compound showing high toxicity must not be used asa catalyst for preparation of urethane materials when the urethanematerials are applied for medical instruments which are used in livingorganism or by contacting with living organism. The organic tin compoundis recognized as a distraction substance for endocrine (environmentalhormone) which is recently topical substance. Accordingly, somecatalysts other than organic tin compounds are earnestly necessitated.

From the viewpoint of mechanical strength and excellent oxygenpermeability, urethane bond-containing siloxane compounds(macromonomers) have been examined for the use as medical instruments,in particular, optical materials such as a contact lens material and anintraocular lens material (Japanese Unexamined Patent Publication No.22487/1979, Japanese Unexamined Patent Publication No. 121826/1994, U.S.Pat. No. 5,451,617 and the like). However, because the siloxanecompounds disclosed in these references are prepared by using theorganic tin compounds almost, these siloxane compounds are not suitableas medical materials on the basis of the above reasons. Even ifpurification of the siloxane compound is carried out, the organic tincompounds remain within the siloxane compound.

Usually, the above urethane bond-containing siloxane compounds(macromonomers) have been prepared by finally introducing a polymerizinggroup in a polyfunctional polysiloxane which is a main chain throughurethane bond (Japanese Unexamined Patent Publication No. 179217/1986,Japanese Unexamined Patent Publication No. 35014/1991 and the like).However, when this method is employed, it is inevitable that thepolymerizing group is inestimably and repeatedly introduced in thepolyfunctional polysiloxane which is a main chain through urethane bond.As a result, molecular weight of the obtained siloxane compound becomeshigher than planned molecular weight. Accordingly, there is a problemthat clear understanding for structure of the obtained compound isdifficult.

Because the above siloxane compound becomes high viscous solutionaccording to its molecular weight or kind of reaction components,effective purification methods for the siloxane compound are notdeveloped. So, it is very difficult to remove impurities such as theabove catalyst and by-products, and crude siloxane compound is used.Accordingly, the use of the siloxane compounds has been feared from theviewpoint of safety, including the above problems.

An object of the present invention is to provide a process for easilypreparing an urethane compound, in particular, while molecular weight ofthe compound is controlled, in the absence of a catalyst or in thepresence of a catalyst showing lower toxicity instead of theconventional organic tin compounds.

This and other objects of the present invention will become apparentfrom the description hereinafter.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a processfor preparing an urethane compound for medical instruments,characterized by

reacting a hydroxyl compound (A) with an isocyanate compound (B) in theabsence of a catalyst or in the presence of a reaction catalyst otherthan an organic tin compound to give an urethane compound (I).

According to the process of the present invention, an urethane compoundshowing high safety, which is very useful for a material of medicalinstruments represented by optical materials can be easily prepared, inparticular, while molecular weight of the compound is controlled.

DETAILED DESCRIPTION

In the process for preparing an urethane compound for medicalinstruments, as mentioned above, the hydroxyl compound (A) is reactedwith the isocyanate compound (B) to give an urethane compound (I) in theabsence of the catalyst or in the presence of the reaction catalystother than the organic tin compound in order to more accelerate thisreaction.

In consideration of the use of the urethane compound as a material formedical instruments, preferable examples of the above reaction catalystare an organic iron compound and an amine compound because of excellentsafety.

Examples of the above organic iron compound are, for instance, iron(III) acetylacetonate and the like.

Examples of the above amine compound are, for instance, a cyclictertiary amine such as triethylenediamine, an aliphatic tertiary aminesuch as trimethylamine or triethylamine, an aromatic tertiary amine suchas dimethylaniline or triphenylamine, and the like.

Because molecular weight of the urethane compound can be moresufficiently controlled, the organic iron compound is particularlypreferable.

In order to sufficiently exhibit acceleration effect for the progress ofreaction, it is desired that the amount of the reaction catalyst is, onthe basis of weight, at least 1 ppm, preferably at least 30 ppm of thetotal amount of the hydroxyl compound (A) and the isocyanate compound(B). In order to prevent removal of the-reaction catalyst from beingfinally difficult after the finish of reaction, it is desired that theamount of the reaction catalyst is, on the basis of weight, at most10000 ppm, preferably at most 3000 ppm of the total amount of thehydroxyl compound (A) and the isocyanate compound (B). The amount of thereaction catalyst can be suitably adjusted within the above rangeaccording to kind of the hydroxyl compound (A) and the isocyanatecompound (B) in urethane reactions (i) and (ii) as mentioned below.

In the present invention, it is desired that the above compound (I) isprepared by, for instance, the following two-step urethane reactions (i)and (ii).

At first, in the urethane reaction (i), at least one member ofdihydroxyl compounds (A-2) is used as the hydroxyl compound (A) and atleast one member of diisocyanate compounds (B-2) is used as theisocyanate compound (B), so the dihydroxyl compound (A-2) is reactedwith the diisocyanate compound (B-2). As a result, at least two urethanebonds are formed between hydroxyl group in the dihydroxyl compound (A-2)and isocyanate group in the diisocyanate compound (B-2).

When 1 mole of the dihydroxyl compound (A-2) is reacted with 2 moles ofthe diisocyanate compound (B-2), two urethane bonds are formed and acompound having isocyanate groups in its both ends respectively throughtwo urethane bonds is synthesized. On the other hand, when 2 moles ofthe dihydroxyl compound (A-2) is reacted with 1 mole of the diisocyanatecompound (B-2), two urethane bonds are formed and a compound havinghydroxyl groups in its both ends respectively through two urethane bondsis synthesized.

In the urethane reaction (i), the dihydroxyl compound (A-2) is notlimited to one member and the diisocyanate compound (B-2) is also notlimited to one member. So, at least two members of each compound can beused with suitable combination. Accordingly, in a compound synthesizedin the urethane reaction (i), units derived from at least two members ofthe dihydroxyl compounds (A-2) and/or units derived from at least twomembers of the diisocyanate compounds (B-2) can be included.

The urethane reaction (i) may be finished only one time or repeatedlycarried out stepwise. When the urethane reaction (i) is repeatedlycarried out stepwise, the number of formed urethane bond is increased onthe basis of the number of reaction.

Typical examples of the dihydroxyl compound (A-2) are, for instance, ahydroxyl group-containing polysiloxane compound represented by theformula (I):

wherein each of R¹ and R² is independently an alkylene group having 1 to20 carbon atoms, each of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ is independently alinear alkyl group having 1 to 20 carbon atoms, a branched alkyl grouphaving 3 to 20 carbon atoms or a cyclic alkyl group having 3 to 20carbon atoms, which may be substituted with fluorine atom, x is aninteger of 1 to 1500, y is an integer of 1 to 1499, and “x+y” is aninteger of 1 to 1500; and the like.

In the above formula (I), each of R¹ and R² is preferably an alkylenegroup having 1 to 10 carbon atoms. Each of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ ispreferably a linear alkyl group which may be substituted with fluorineatom, having 1 to 5 carbon atoms, a branched alkyl group which may besubstituted with fluorine atom, having 3 to 5 carbon atoms, or a cyclicalkyl group which may be substituted with fluorine atom, having 3 to 5carbon atoms. Also, x is preferably an integer of 1 to 500, y ispreferably an integer of 1 to 499, and “x+y” is preferably an integer of1 to 500.

In addition, as the above dihydroxyl compound (A-2), a dihydroxylcompound having hydroxyl groups in its both ends, such as a polyalkyleneglycol such as polyethylene glycol or polypropylene glycol; and the likeare exemplified.

Typical examples of the diisocyanate compound (B-2) are, for instance, adiisocyanate compound represented by the formula (II):

O═C═N—R¹⁰—N═C═O  (II)

wherein R¹⁰ is a linear aliphatic hydrocarbon group having 1 to 20carbon atoms, a branched hydrocarbon group having 2 to 20 carbon atoms,a cyclic aliphatic hydrocarbon group having 3 to 20 carbon atoms or anaromatic hydrocarbon group having 6 to 20 carbon atoms; and the like.

In the above formula (II), R¹⁰ is preferably a linear aliphatichydrocarbon group having 1 to 12 carbon atoms, a branched hydrocarbongroup having 2 to 12 carbon atoms, a cyclic aliphatic hydrocarbon grouphaving 3 to 12 carbon atoms or an aromatic hydrocarbon group having 6 to12 carbon atoms.

Concrete examples of the diisocyanate compound (B-2) are, for instance,ethylenediisocyanate, isophoronediisocyanate,1,6-hexamethylenediisocyanate, 1,2-toluenediisocyanate,1,4-toluenediisocyanate, xylylenediisocyanate, bis(2-isocyanatethyl)fumarate, 1,5-naphthalenediisocyanate, cyclohexyl-1,4-diisocyanate,4,4′-dicyclohexylmethanediisocyanate, diphenylmethane-4,4′-diisocyanate,2,2,4-(2,4,4)-trimethylhexane-1,6-diisocyanate and the like.

It is considered that the ratio of the dihydroxyl compound (A-2) to thediisocyanate compound (B-2) in the urethane reaction (i) considerablyeffects for the amount of prepared by-products, the amount of residualnon-reacted compounds, and molecular weight and molecular weightdistribution of the aimed urethane compound.

In the urethane reaction (i), from the viewpoint of reduction ofresidual non-reacted isocyanate groups, it is desired that the totalamount of hydroxyl group in the dihydroxyl compound (A-2) based on 1mole of isocyanate group in the diisocyanate compound (B-2) is at least0.4 mole, preferably at least 0.6 mole, more preferably at least 0.8mole. From the viewpoint of reduction of residual non-reacted dihydroxylcompound (A-2) which not bonds to the diisocyanate compound (B-2)through urethane bond, it is desired that the total amount of hydroxylgroup in the dihydroxyl compound (A-2) based on 1 mole of isocyanategroup in the diisocyanate compound (B-2) is at most 2 moles, preferablyat most 1.5 moles, more preferably at most 1.25 moles.

The amount of the dihydroxyl compound (A-2) and the diisocyanatecompound (B-2) is adjusted within the above range. Then, these compoundsare reacted by stirring and mixing with each other.

In the above reaction, reaction temperature and reaction time are notparticularly limited and suitably adjusted according to kind andcombination of each compound. In order to prevent insufficient reaction,it is desired that reaction time is at least 1 minute, preferably atleast 30 minutes, and reaction temperature is at least −30° C.,preferably at least 0° C. In order to prevent polymerization due topolymerizable compounds during reaction, it is desired that reactiontime is at most 100 hours, preferably at most 50 hours, and reactiontemperature is at most 150° C., preferably at most 100° C.

Then, in the urethane reaction (ii),

(a) the compound having isocyanate groups in its both ends obtained inthe above urethane reaction (i) is reacted with at least one member ofmonohydroxyl compounds (A-1) as the hydroxyl compound (A) to formurethane bond; or

(b) the compound having hydroxyl groups in its both ends obtained in theabove urethane reaction (i) is reacted with at least one member ofmonoisocyanate compounds (B-1) as the isocyanate compound (B) to formurethane bond. By each reaction, the compound (I) having at least foururethane bonds is prepared.

Because molecular weight of the aimed urethane compound can becontrolled and structure of this compound can be exactly clarified, itis desired that the above two-step urethane reactions (i) and (ii) arecarried out in the present invention.

In the above reaction (a), the monohydroxyl compound (A-1) to be reactedwith the compound having isocyanate groups in its both ends is notlimited to one member. At least two members of the monohydroxylcompounds (A-1) can be suitably used. In the above reaction (b), themonoisocyanate compound (B-1) to be reacted with the compound havinghydroxyl groups in its both ends is not limited to one member. At leasttwo members of the monoisocyanate compounds (B-1) can be suitably used.As a result, the compound (I) obtained in the reaction (a) or (b) cancontain the unit derived from two members of the monohydroxyl compounds(A-1) or the unit derived from two members of the monoisocyanatecompounds (B-1).

In accordance that the above urethane reaction (i) is finished only onetime or repeatedly carried out stepwise, the number of urethane bond andthe number of unit (block) derived from each component in the compound(I) synthesized in the urethane reaction (ii) vary. As a result, forinstance, a diblock-type compound (I) is synthesized. Because chainlength of each segment in the diblock-type compound (I) is controlled,various different effects can be exhibited.

Typical examples of the monohydroxyl compound (A-1) are, for instance, acompound having hydroxyl group and an active unsaturated group, such asa hydroxyalkyl (meth)acrylate, allyl alcohol, vinylbenzyl alcohol,monohydroxyl fumarate, monohydroxyl maleate or monohydroxyl itaconate;and the like.

In consideration of copolymerizability of the aimed compound (I) withthe other copolymerizable compound having an active unsaturated group,among the above exemplified compounds, a hydroxyalkyl (meth)acrylate ispreferable. Concrete examples of the hydroxyalkyl (meth)acrylate are,for instance, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl(meth)acrylate, 3-hydroxypropyl (meth)acrylate, 4-hydroxybutyl(meth)acrylate and the like.

Typical examples of the monoisocyanate compound (B-1) are, for instance,a compound having isocyanate group and an active unsaturated group, suchas allylisocyanate, vinylisocyanate, vinylbenzylisocyanate or2-isocyanatethyl (meth)acrylate; and the like.

When the above reaction (b) in the urethane reaction (ii) is carriedout, because the number of urethane bond in the compound (I) can becontrolled and mechanical strength can be imparted to the compound (I),it is desired that a compound containing a monoisocyanate compound(B-1-1) prepared by reacting the diisocyanate compound (B-2) with themonohydroxyl compound (A-1) is used as the monoisocyanate compound(B-1). It is particularly desired that only the monoisocyanate compound(B-1-1) is used as the monoisocyanate compound (B-1).

In the reaction (a), it is desired that the ratio of the compound havingisocyanate groups in its both ends to the monohydroxyl compound (A-1) isadjusted so as to react isocyanate groups in the compound havingisocyanate groups in its both ends with almost neither more nor lesshydroxyl groups in the monohydroxyl compound (A-1). For instance, fromthe viewpoint of reduction of residual non-reacted isocyanate groups, itis desired that the amount of hydroxyl group in the monohydroxylcompound (A-1) based on 1 mole of isocyanate group in the compoundhaving isocyanate groups in its both ends is at least 1.0 mole,preferably at least 1.1 moles, more preferably at least 1.2 moles. Fromthe viewpoint of reduction of residual non-reacted monohydroxyl compound(A-1) which not bonds to the compound having isocyanate groups in itsboth ends through urethane bond, it is desired that the amount ofhydroxyl group in the monohydroxyl compound (A-1) based on 1 mole ofisocyanate group in the compound having isocyanate groups in its bothends is at most 2.0 moles, preferably at most 1.75 moles, morepreferably at most 1.5 moles.

The amount of the compound having isocyanate groups in its both ends andthe monohydroxyl compound (A-1) is adjusted within the above range.Then, these compounds are reacted by stirring and mixing with eachother.

In the above reaction, reaction temperature and reaction time are notparticularly limited and suitably adjusted according to kind andcombination of each compound. In order to prevent insufficient reaction,it is desired that reaction time is at least 1 minute, preferably atleast 30 minutes, and reaction temperature is at least −30° C.,preferably at least 0° C. In order to prevent polymerization due topolymerizable compounds during reaction, it is desired that reactiontime is at most 100 hours, preferably at most 50 hours, and reactiontemperature is at most 150° C., preferably at most 100° C.

In the reaction (b), it is desired that the ratio of the compound havinghydroxyl groups in its both ends to the monoisocyanate compound (B-1) isadjusted so as to react hydroxyl groups in the compound having hydroxylgroups in its both ends with almost neither more nor less isocyanategroups in the monoisocyanate compound (B-1). For instance, from theviewpoint of reduction of residual non-reacted hydroxyl groups, it isdesired that the amount of isocyanate group in the monoisocyanatecompound (B-1) based on 1 mole of hydroxyl group in the compound havinghydroxyl groups in its both ends is at least 1.0 mole, preferably atleast 1.1 moles, more preferably at least 1.2 moles. From the viewpointof reduction of residual non-reacted monoisocyanate compound (B-1) whichnot bonds to the compound having hydroxyl groups in its both endsthrough urethane bond, it is desired that the amount of isocyanate groupin the monoisocyanate compound (B-1) based on 1 mole of hydroxyl groupin the compound having hydroxyl groups in its both ends is at most 2.0moles, preferably at most 1.75 moles, more preferably at most 1.5 moles.

The amount of the compound having hydroxyl groups in its both ends andthe monoisocyanate compound (B-1) is adjusted within the above range.Then, these compounds are reacted by stirring and mixing with eachother.

In the above reaction, reaction temperature and reaction time are notparticularly limited and suitably adjusted according to kind andcombination of each compound. In order to prevent insufficient reaction,it is desired that reaction time is at least 1 minute, preferably atleast 30 minutes, and reaction temperature is at least −30° C.,preferably at least 0° C. In order to prevent polymerization due topolymerizable compounds during reaction, it is desired that reactiontime is at most 100 hours, preferably at most 50 hours, and reactiontemperature is at most 150° C., preferably at most 100° C.

When the compound (I) is prepared by the urethane reaction (i) or (ii),in order to prevent active unsaturated groups in each compound frompolymerizing with each other, it is desired that a polymerizationinhibitor is suitably used.

Examples of the polymerization inhibitor are, for instance, a stableradical compound; an addition inhibitor such as oxygen, a benzoquinonederivative or a nitro compound; and the like. Hydroquinone,p-methoxyphenol and butylhydroxtoluene are preferably exemplified. It isdesired that the amount of the polymerization inhibitor based on 100parts by weight (hereinafter referred to as “part(s)”) of all thecompounds having an active unsaturated group is about 0.01 to 1 part.

The hydroxyl compound (A) can be reacted with the isocyanate compound(B) in the absence of a solvent or in the presence of an organicsolvent.

Examples of the organic solvent are, for instance, tetrahydrofuran,benzene, toluene, acetonitrile, methylene chloride and the like.

When the organic solvent is used, in order to remove the fear that itbecomes difficult to react the hydroxyl compound (A) with the isocyanatecompound (B), and so, the yield of the compound (I) is lowered, it isdesired that the total concentration of the hydroxyl compound (A) andthe isocyanate compound (B) in the organic solvent is at least 0.01mol/L, preferably at least 0.1 mol/L. That is, the amount (volume) ofthe organic solvent can be calculated according to the totalconcentration of the hydroxyl compound (A) and the isocyanate compound(B). A reaction solution composed of the hydroxyl compound (A), theisocyanate compound (B) and the organic solvent is sufficiently stirredor shaken so that the reaction uniformly proceeds.

In accordance with the above steps, the aimed urethane compound (I) canbe prepared. After finishing the reaction for preparing the compound(I), it is desired that the compound (I) is purified by removingnon-reacted compounds, compounds having lower molecular weight(by-products) and catalysts.

For purification of the compound (I), an organic solvent is preferablyused. In addition, the compound (I) can be purified by using asupercritical fluid with referring to “Polymer Applications, Vol. 43,No. 11, p. 38 (1994)”.

As the above organic solvent for purification, a solvent which candissolve the non-reacted compounds, by-products and catalysts or candissolve the compound (I) is used. Typical examples of the organicsolvent are, for instance, methanol, ethanol, acetone, tetrahydrofuran,acetonitrile, methylene chloride, hexane and the like. These can be usedalone or in admixture thereof. In order to more effectively purify thecompound (I), a mixed solvent of hexane and methanol and a mixed solventof hexane and acetonitrile are preferably used.

In order to sufficiently remove the non-reacted compounds, by-productsand catalysts, it is desired that the amount of the organic solvent is,on the basis of the volume, at least {fraction (1/20)} time, preferablyat least {fraction (1/10)} time of the amount of the compound (I). Inorder to prevent the amount of waste fluid from increasing afterpurification, it is desired that the amount of the organic solvent is,on the basis of the volume, at most 20 times, preferably at most 10times of the amount of the compound (I).

As the above supercritical fluid for purification, a fluid in thesupercritical state, such as carbon dioxide, ethane or propane may becited.

Condition as to purification with the supercritical fluid variesaccording to molecular weight and chemical structure of the compound(I). So, the condition cannot be sweepingly determined. For instance, itis desired that treating pressure is 5 to 100 MPa, and treatingtemperature is 0° to 100° C.

In order to more effectively extract the compounds having lowermolecular weight, an auxiliary for extraction can be used duringpurification of the compound (I) with the supercritical fluid. Examplesof the auxiliary for extraction are, for instance, acetonitrile,methanol and the like.

According to the process of the present invention, the urethane compoundshowing high safety, which is very useful for a material of medicalinstruments represented by optical materials can be easily prepared, inparticular, while molecular weight of the compound is controlled.

The process for preparing an urethane compound for medical instrumentsof the present invention is more specifically described and explained bymeans of the following Examples. It is to be understood that the presentinvention is not limited to the Examples, and various changes andmodifications may be made in the invention without departing from thespirit and scope thereof.

EXAMPLE 1

(1) Synthesis of HEA-IPDI

With a 1 L three-necked flask of which side tubes previously substitutedwith nitrogen gas were equipped with Dimroth reflux condenser, amechanical stirrer and a thermometer was charged 66.69 g (0.3 mole) ofisophoronediisocyanate (hereinafter referred to as “IPDI”).

Then, to IPDI in the three-necked flask was added 41.80 g (0.36 mole) of2-hydroxyethyl acrylate (hereinafter referred to as “HEA”) in which0.0110 g of iron (III) acetylacetonate (hereinafter referred to as“FeAA”) was previously dissolved.

To the mixture in the three-necked flask was added 0.220 g ofp-methoxyphenol (hereinafter referred to as “MEHQ”) as a polymerizationinhibitor and then, the reaction solution in the three-necked flask wascontinuously stirred in an oil bath prescribed at 50° C. After about 3hours, ¹H-NMR spectrum of a sample from the reaction solution wasexamined and then, the aimed compound (HEA-IPDI) was recognized. Data of¹H-NMR spectrum are as follows:

¹H-NMR (CDCl₃, δ ppm) 2.90 (NH—CH₂, 2H, m) 3.02 (CH₂—N═C═O, 2H, s) 3.05(Raw material, CH₂—N═C═O, 2H, s) 4.27-4.33 (—(O)CO—CH₂—, 4H, m) 4.61(NH, 1H, s) 4.87 (NH, 1H, s) 5.84 (CH═, 1H, dd) 6.13 (CH═, 1H, dd) 6.42(CH═, 1H, dd)

(2) Reaction of HEA-IPDI with Polydimethylsiloxane Containing HydroxylGroups in its Both Ends (Synthesis of compound (I))

To a reaction solution containing about 60.8 g of the above compound(HEA-IPDI) (amount of isocyanate group: 0.18 mole) in the three-neckedflask was added 325.80 g (converted amount of hydroxyl group: 0.09 mole)of polydimethylsiloxane containing hydroxyl groups in its both ends(polymerization degree: 40, number average molecular weight: 3100, codename: KF-6002, made by Shin-Etsu Chemical Co., Ltd.; hereinafterreferred to as “DHDMSi-40”) in which 0.0330 g of FeAA was previouslydissolved. Then, the reaction solution was continuously stirred in theoil bath heated to 80° C.

After about 4 hours, ¹H-NMR spectrum and FT/IR spectrum of a sample fromthe reaction solution were examined. Then, structural analysis wascarried out by using these spectra, so that the aimed compound (I) wasrecognized. Data of ¹H-NMR spectrum and FT/IR spectrum are as follows:

¹H-NMR (CDCl₃, δ ppm) 0.06 (Si—CH₃, 3H, m) 0.52 (Si—CH₂, 2H, m) 2.91(NH—CH₂, 2H, d) 3.02 (Intermediate, CH₂—N═C═O, 2H, s) 3.42 (—O—CH₂, 2H,t) 3.62 (—O—CH₂, 2H, m) 4.18-4.34 (—(O)CO—CH₂—, 6H, m) 4.54 (NH, 1H, s)4.85 (NH, 1H, s) 5.84 (CH═, 1H, dd) 6.14 (CH═, 1H, dd) 6.43 (CH═, 1H,dd)

FT/IR (cm⁻¹) 1262 and 802 (Si—CH₃) 1094 and 1023 (Si—O—Si) 1632 (C═C)near 1728 (C═O, ester and urethane) 2227 (N═C═O)

The number average molecular weight of the compound (I) was measured bysize exclusion chromatography (hereinafter referred to as “SEC”), andthe amount of by-products (compounds having lower molecular weight) wascalculated from the area ratio in chromatogram by SEC. The results areshown in TABLE 1.

(3) Purification of Compound (I) with Organic Solvent(n-Hexane/Acetonitrile) (Preparation of Purified Urethane Compound)

Into a 5 L separatory funnel equipped with a side tube was transferredabout 400 g of the compound (I) which was previously dissolved in 2 L ofn-hexane. Then, 300 mL of acetonitrile was added to the solution in theseparatory funnel. After the mixture solution in the separatory funnelwas stirred at about 500 rpm for 20 minutes, the mixture solution wasallowed to stand. After about 1 hour, it was recognized that thecontents in the separatory funnel were separated to two layers. Then,acetonitrile layer (lower layer) was removed.

Hexane layer was washed with 50 mL of acetonitrile. The wash wasrepeated two times. It was recognized that the hexane layer wascolorless and transparent. After the acetonitrile layer was removed, thehexane layer was collected into a 1 L brown pear shaped flask of whichdry weight was previously weighed, and the solvent was evaporated underthe vacuum. Then, the contents in the pear shaped flask were driedovernight by using a pressure reducing dryer to give 318.49 g of apurified urethane compound. The yield of the purified compound was 83%.

¹H-NMR spectrum and FT/IR spectrum of the above purified urethanecompound were examined. Then, structural analysis was carried out byusing these spectra, so that the aimed compound was recognized. Data of¹H-NMR spectrum and FT/IR spectrum are as follows:

¹H-NMR (CDCl₃, δ ppm) 0.06 (Si—CH₃, 3H, m) 0.52 (Si—CH₂, 2H, m) 2.91(NH—CH₂, 2H, d) 3.42 (—O—CH₂, 2H, t) 3.61 (—O—CH₂, 2H, m) 4.18-4.34(—(O)CO—CH₂—, 6H, m) 4.54 (NH, 1H, s) 4.85 (NH, 1H, s) 5.84 (CH═, 1H,dd) 6.14 (CH═, 1H, dd) 6.43 (CH═, 1H, dd)

FT/IR (cm⁻¹) 1262 and 802 (Si—CH₃) 1094 and 1023 (Si—O—Si) 1632 (C═C)near 1728 (C═O, ester and urethane)

The number average molecular weight of the purified urethane compoundwas measured by SEC, and the amount of by-products (compounds havinglower molecular weight) was calculated from the area ratio inchromatogram by SEC. The results are shown in TABLE 1.

Cellular toxicity of the above compound (I), and transparency of thecompound (I) and the purified urethane compound were examined. Theresults are shown in TABLE 1.

¹H-NMR analysis, FT/IR analysis, SEC analysis, evaluation oftransparency and cellular toxicity test were carried out in accordancewith the following methods, respectively.

(I) ¹H-NMR Analysis

¹H-NMR spectrum was examined under the following conditions.

Fourier Transform NMR Spectrometer:

GEMINI2000/400BB type, made by Varian Technologies Limited

Nuclear:

¹H (resonance frequency: 400.42 MHz)

Solvent:

CDCl₃

Test Sample:

About 5 to 10 w/v % CDCl₃ solution

Measuring Temperature:

About 22° C.

(II) FT/IR Analysis

FT/IR spectrum was examined under the following conditions.

Infrared Spectrophotometer:

FT/IR-8300, made by Nippon Bunko Kabushiki Kaisha

Method:

KBr disk method

(III) SEC Analysis

SEC analysis was carried out under the following conditions.

SEC System:

Made by Nippon Bunko Kabushiki Kaisha

Column oven: 860-CO made by Nippon Bunko Kabushiki Kaisha

Degasser: DG-980-50 made by Nippon Bunko Kabushiki Kaisha

Pump: PU-980 made by Nippon Bunko Kabushiki Kaisha

Detector (RI type): 830-RI made by Nippon Bunko Kabushiki Kaisha

(UV type): SPD-10A made by SHIMAZU CORPORATION

Column:

Ultrastyragel Plus MX 10³ Å made by Waters Co.

(two columns connected in series)

Eluent:

Tetrahydrofuran

Calibration Curve:

Produced by using standard polystyrene

(IV) Evaluation of Transparency

The test sample was observed with naked eye.

(V) Cellular Toxicity Test (Test as to Prevention for Preparation ofColony)

The test was carried out in accordance with the guideline of “Basicbiological test of medical instruments and medical materials” (MEDICALDEVICES DIVISION PHARMACEUTICAL AFFAIRS BUREAU Notification No. 99,1995, published on Jun. 27, 1995 in Japan). Then, biological safety ofthe test sample was evaluated.

EXAMPLE 2

A compound (I) was prepared in same manner as in EXAMPLE 1 except that180 g (converted amount of hydroxyl group 0.09 mole) ofpolydimethylsiloxane containing hydroxyl groups in its both ends(polymerization degree: 20, number average molecular weight: 2000, codename: KF-6001, made by Shin-Etsu Chemical Co., Ltd.; hereinafterreferred to as “DHDMSi-20”) was used instead of DHDMSi-40. Then, thesame manner as in EXAMPLE 1 was repeated to give 233.7 g of a purifiedurethane compound. The yield of the purified compound was 81%.

Structure of the compound (I) and the purified urethane compound wasexamined and confirmed in the same manner as in EXAMPLE 1. Properties ofthe compound (I) and the purified urethane compound, and the amount ofcompounds having lower molecular weight (by-products) were examined inthe same manner as in EXAMPLE 1. The results are shown in TABLE 1.

EXAMPLE 3

The same manner as in EXAMPLE 1 was repeated except that 77.4 g (0.3mole) of 4,4′-dicyclohexylmethanediisocyanate (hereinafter referred toas “DCHMDI”) was used instead of IPDI to give a compound (HEA-DCHMDI).Then, a compound (I) was prepared in the same manner as in EXAMPLE 1except that HEA-DCHMDI was used instead of HEA-IPDI. Furthermore, thesame manner as in EXAMPLE 1 was repeated to give 333.8 g of a purifiedurethane compound. The yield of the purified compound was 75%.

Structure of the compound (HEA-DCHMDI), the compound (I) and thepurified urethane compound was examined and confirmed in the same manneras in EXAMPLE 1. Properties of the compound (I) and the purifiedurethane compound, and the amount of compounds having lower molecularweight (by-products) were examined in the same manner as in EXAMPLE 1.The results are shown in TABLE 1.

Comparative Example 1 Method Using Organic Tin Compound as ReactionCatalyst

A compound (HEA-IPDI) was prepared in same manner as in EXAMPLE 1 exceptthat 0.011 g of dibutyltin dilaurate (hereinafter referred to as “BSnL”)was used instead of FeAA. Then, a compound (I) was prepared in the samemanner as in EXAMPLE 1 except that 0.033 g of BSnL was used instead ofFeAA. Furthermore, the same manner as in EXAMPLE 1 was repeated to give373.5 g of a purified urethane compound. The yield of the purifiedcompound was 86%.

Structure of the compound (HEA-IPDI), the compound (I) and the purifiedurethane compound was examined and confirmed in the same manner as inEXAMPLE 1. Properties of the compound (I) and the purified urethanecompound, and the amount of compounds having lower molecular weight(by-products) were examined in the same manner as in EXAMPLE 1. Theresults are shown in TABLE 1.

Then, the amount of tin contained in the purified urethane compound wasquantitated by polarographic analysis method. As a result, the amount oftin contained in the purified urethane compound was 40 ppm on the basisof weight. Now, the amount of tin used for starting synthesis of thecompound (I) was about 100 ppm on the basis of weight.

TABLE 1 Amount of Number compound Kind of average having lower Ex.reaction Kind of molecular molecular weight Cellular No. catalystcompound weight (% by weight) Transparency toxicity 1 FeAA Compound (I)4600 23 Colorless and Negative transparent Purified 5800 0.6 Colorlessand compound transparent 2 FeAA Compound (I) 3400 21 Colorless andNegative transparent Purified 4400 1.2 Colorless and compoundtransparent 3 FeAA Compound (I) 4700 27 Colorless and Negativetransparent Purified 5900 2.2 Colorless and compound transparent Com.BSnL Compound (I) 4500 22 Colorless and Positive Ex. transparent No. 1Purified 5800 6.4 Colorless and compound transparent

From the results shown in TABLE 1, it can be understood that accordingto the process of the present invention in EXAMPLES 1 to 3, the urethanecompound showing low toxicity can be easily prepared while molecularweight of the compound is controlled. In addition, it can be understoodthat the amount of the compound having lower molecular weight(by-product) is considerably small in EXAMPLES 1 to 3.

To the contrary, it can be understood that according to the processwherein the organic tin compound is used as the reaction catalyst inCOMPARATIVE EXAMPLE 1, the amount of tin contained in the aimed purifiedurethane compound is large, toxicity of the purified urethane compoundis high and the amount of the compound having lower molecular weight(by-product) is large.

EXAMPLE 4

(1) Synthesis of HEA-IPDI

With a 1 L three-necked flask of which side tubes previously substitutedwith nitrogen gas were equipped with Dimroth reflux condenser, amechanical stirrer and a thermometer was charged 33.33 g (0.15 mole) ofIPDI.

Then, to IPDI in the three-necked flask was added 17.40 g (0.15 mole) ofHEA in which 0.06 g of triethylenediamine (hereinafter referred to as“TEDA”) was previously dissolved.

To the mixture in the three-necked flask was added 0.09 g of MEHQ as apolymerization inhibitor and then, the reaction solution in thethree-necked flask was continuously stirred in an oil bath prescribed at50° C. After about 3 hours, ¹H-NMR spectrum of a sample from thereaction solution was examined and then, the aimed compound (HEA-IPDI)was recognized. Data of ¹H-NMR spectrum are as follows:

¹H-NMR (CDCl₃, δ ppm) 2.90 (NH—CH₂, 2H, m) 3.02 (CH₂—N═C═O, 2H, s) 3.05(Raw material, CH₂—N═C═O, 2H, s) 4.27-4.33 (—(O)CO—CH₂—, 4H, m) 4.61(NH, 1H, s) 4.87 (NH, 1H, s) 5.84 (CH═, 1H, dd) 6.13 (CH═, 1H, dd) 6.42(CH═, 1H, dd)

(2) Reaction of HEA-IPDI with Polydimethylsiloxane Containing HydroxylGroups in its Both Ends (Synthesis of Compound (I))

To a reaction solution containing about 50 g of the above compound(HEA-IPDI) (amount of isocyanate group: 0.1 mole) in the three-neckedflask was added 271.50 g (converted amount of hydroxyl group: 0.075mole) of DHDMSi-40 in which 0.30 g of TEDA was previously dissolved.Then, the reaction solution was continuously stirred in the oil bath at50° C.

After about 6 hours, ¹H-NMR spectrum and FT/IR spectrum of a sample fromthe reaction solution were examined. Then, structural analysis wascarried out by using these spectra, so that the aimed compound (I) wasrecognized. Data of ¹H-NMR spectrum and FT/IR spectrum are as follows:

¹H-NMR (CDCl₃, δ ppm) 0.06 (Si—CH₃, 3H, m) 0.52 (Si—CH₂, 2H, m) 2.91(NH—CH₂, 2H, d) 3.02 (Intermediate, CH₂—N═C═O, 2H, s) 3.42 (—O—CH₂, 2H,t) 3.61 (—O—CH₂, 2H, m) 4.18-4.34 (—(O)CO—CH₂—, 6H, m) 4.54 (NH, 1H, s)4.85 (NH, 1H, s) 5.84 (CH═, 1H, dd) 6.14 (CH═, 1H, dd) 6.43 (CH═, 1H,dd) FT/IR (cm⁻¹) 1262 and 802 (Si—CH₃) 1094 and 1023 (Si—O—Si) 1632(C═C) near 1728 (C═O, ester and urethane) 2227 (N═C═O)

The number average molecular weight of the compound (I) was measured inthe same manner as in EXAMPLE 1. As a result, the number averagemolecular weight was 4300.

(3) Purification of Compound (I) with Organic Solvent(n-Hexane/Methanol) (Preparation of Purified Urethane Compound)

Into a 5 L separatory funnel equipped with a side tube was transferredabout 300 g of the compound (I) which was previously dissolved in 2 L ofn-hexane. Then, 300 mL of distilled water was added to the solution inthe separatory funnel. After the mixture solution in the separatoryfunnel was stirred at about 500 rpm for 20 minutes, the mixture solutionwas allowed to stand. After about 1 hour, it was recognized that thecontents in the separatory funnel were separated to two layers. Then,water layer (lower layer) was removed.

Then, 300 mL of methanol was added to hexane layer in the separatoryfunnel, and after the mixture solution in the separatory funnel wasstirred at about 500 rpm for 20 minutes, the mixture solution wasallowed to stand. After about 1 hour, it was recognized that thecontents in the separatory funnel were separated to two layers. Then,methanol layer (lower layer) was removed.

Hexane layer was washed with 50 mL of methanol. The wash was repeatedtwo times. After the methanol layer was removed, the hexane layer wascollected into a 1 L brown pear shaped flask of which dry weight waspreviously weighed, and the solvent was removed by a rotatingevaporator. Then, the contents in the pear shaped flask were driedovernight by using a pressure reducing dryer to give 220 g of a purifiedurethane compound. The yield of the purified compound was 70%.

¹H-NMR spectrum and FT/IR spectrum of the above purified urethanecompound were examined. Then, structural analysis was carried out byusing these spectra, so that the aimed compound was recognized. Data of¹H-NMR spectrum and FT/IR spectrum are as follows:

¹H-NMR (CDCl₃, δ ppm) 0.06 (Si—CH₃, 3H, m) 0.52 (Si—CH₂, 2H, m) 2.91(NH—CH₂, 2H, d) 3.42 (—O—CH₂, 2H, t) 3.61 (—O—CH₂, 2H, m) 4.18-4.34(—(O)CO—CH₂—, 6H, m) 4.54 (NH, 1H, s) 4.85 (NH, 1H, s) 5.84 (CH═, 1H,dd) 6.14 (CH═, 1H, dd) 6.43 (CH═, 1H, dd) FT/IR (cm⁻¹) 1262 and 802(Si—CH₃) 1094 and 1023 (Si—O—Si) 1632 (C═C) near 1728 (C═O, ester andurethane)

The number average molecular weight of the purified urethane compoundwas measured in the same manner as in EXAMPLE 1. As a result, the numberaverage molecular weight was 6000.

Cellular toxicity of the above compound (I) was examined in the samemanner as in EXAMPLE 1. As a result, the compound (I) showed negative.So, it can be understood that the urethane compound in EXAMPLE 4 showslower toxicity.

In addition to the ingredients used in the Examples, other ingredientscan be used in the Examples as set forth in the specification to obtainsubstantially the same results.

What is claimed is:
 1. A process for preparing a urethane compound formedical instruments comprising the steps of a) preparing a urethanecompound by reacting at least one hydroxyl compound and at least oneisocyanate compound in the presence of an organic iron compound, and b)removing the organic iron compound from the urethane compound obtainedin the step a).
 2. The process for preparing a urethane compound ofclaim 1 wherein the organic iron compound is represented by thefollowing formula (I)

in which each of R¹ and R² is methyl group.
 3. The process for preparinga urethane compound of claim 1 wherein the organic iron compound isremoved by using an organic solvent or a supercritical fluid.
 4. Theprocess for preparing a urethane compound of claim 1 wherein theurethane compound obtained in the step b) has a radical polymerizableethylenic unsaturated group.
 5. The process for preparing a urethanecompound of claim 1 wherein at least one of the hydroxyl compound or atleast one of the isocyanate compound has a siloxane structure having arepetition number of 1 to 1500.